Treatment of neurocysticercosis: Current status and future research needs

Treatment of neurocysticercosis:Current status and future research needs

T.E. Nash, MD, G. Singh, MD, A.C. White, MD, V. Rajshekhar, MCh, J.A. Loeb, MD, PhD, J.V.Proaño, MD, O.M. Takayanagui, MD, A.E. Gonzalez, DVM, PhD, J.A. Butman, MD, PhD, C.DeGiorgio, MD, O.H. Del Brutto, MD, A. Delgado-Escueta, MD, PhD, C.A.W. Evans, MD,PhD, R.H. Gilman, MD, DTMH, S.M. Martinez, MD, M.T. Medina, MD, E.J. Pretell, MD, J.Teale, PhD, and H.H. Garcia, MD, PhDLaboratory of Parasitic Diseases (T.E.N.), National Institute of Allergy and Infectious Diseases,NIH, Bethesda, MD; Dayanand Medical College and Hospital (G.S.), Ludhiana, Punjab, India;Infectious Disease Section (A.C.W.), Department of Medicine, Baylor College of Medicine,Houston, TX; Department of Neurological Sciences (V.R.), Christian Medical College andHospital, Vellore, India; Department of Neurology and Center for Molecular Medicine andGenetics (J.A.L.), Wayne State University School of Medicine, Detroit, MI; Medical Research Unitfor Neurologic Diseases (J.V.P.), Hospital de Especialidades, Centro Medico Nacional Siglo XXI,Mexican Institute of Social Security, Mexico City; Department of Neurology (O.M.T.), School ofMedicine of Ribeirao Preto, Universidade de Sao Paulo, Ribeirão Preto, Brazil; School ofVeterinary Medicine (A.E.G.), Universidad Nacional Mayor de San Marcos, Lima, Perú;Department of International Health (A.E.G., R.H.G., H.H.G.), Johns Hopkins UniversityBloomberg School of Hygiene and Public Health, Baltimore, MD; Diagnostic RadiologyDepartment (J.A.B.), Warren G. Magnuson Clinical Center, NIH, Bethesda, MD; Department ofNeurology (C.D.G., A.D.-E.), Reed Neurological Research Center, UCLA, Los Angeles, CA;Department of Neurological Sciences (O.H.D.B.), Hospital-Clínica Kennedy, Guayaquil, Ecuador;VA Epilepsy Center of Excellence (A.D.-E.), Los Angeles, CA; University of Cambridge ClinicalSchool (C.A.W.E.), Cambridge, and Department of Infectious Diseases and Microbiology,Imperial College London, London, UK; Department of Microbiology (R.H.G., E.J.P., H.H.G.),Universidad Peruana Cayetano Heredia, Lima, Perú; Cysticercosis Unit (S.M.M., H.H.G.),Instituto Especializado en Ciencias Neurológicas, Lima, Peru; Universidad Nacional Autonoma deHonduras (M.T.M.), Tegucigalpa, Honduras; and Department of Microbiology and Immunology(J.T.), University of Texas Health Science Center, San Antonio.

AbstractHere we put forward a roadmap that summarizes important questions that need to be answered todetermine more effective and safer treatments. A key concept in management ofneurocysticercosis is the understanding that infection and disease due to neurocysticercosis arevariable and thus different clinical approaches and treatments are required. Despite recentadvances, treatments remain either suboptimal or based on poorly controlled or anecdotalexperience. A better understanding of basic pathophysiologic mechanisms including parasitesurvival and evolution, nature of the inflammatory response, and the genesis of seizures, epilepsy,and mechanisms of anthelmintic action should lead to improved therapies.

Copyright © 2006 by AAN Enterprises, Inc.

Address correspondence and reprint requests to Dr. T.E. Nash, Laboratory of Parasitic Diseases, National Institute of Allergy andInfectious Diseases, NIH, Bethesda, MD; [email protected].

Disclosure: The authors report no conflicts of interest.

Europe PMC Funders GroupAuthor ManuscriptNeurology. Author manuscript; available in PMC 2010 August 17.

Published in final edited form as:Neurology. 2006 October 10; 67(7): 1120–1127. doi:10.1212/01.wnl.0000238514.51747.3a.

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Cysticercosis, the most common cause of adult-onset epilepsy in the developing world,1-3 isdue to infection with the cystic larval form of the tapeworm Taenia solium. The intestinaldwelling tapeworm stage develops following the ingestion of raw or poorly cooked porkcontaining cystic larvae. The tapeworm releases infectious ova into the feces. When ingestedby free-roaming pigs, the ova release the invasive larvae, which migrate and develop intocystic larvae in the muscles, brain, and other tissues of the pig. Like the pig, humans alsodevelop larval cysts in their tissue after accidental ingestion of ova. Most of the symptomsand disease in humans result from infection of the CNS by larval cysts. Presentingsymptoms and signs can be particularly varied due to differences in location, number ofcysts, and associated inflammation.1,4

Treatment of neurocysticercosis (NCC) is controversial.1,4-9 There are limited naturalhistory studies of most types of NCC so that the benefits of treatments, until most recently,have not been based on optimally designed studies. Despite this imperfect supportinginformation, clinical observations indicate that treatment approaches and requirements differamong the forms or types of NCC. Factors considered in deciding treatments include theanatomic location of cysts, the stage of evolution of the cysts, number of cysts, the degree ofassociated inflammation, size, and severity of symptoms. Frequently, the presence ofmultiple cysts in different anatomic locations and in varying stages of evolution furthercomplicates treatment decisions. Determining effective treatments is complicated by the factthat cysticidal treatment itself initiates a host inflammatory response that may result in thesymptoms that one is trying to control.

Like many complex diseases that evolve over a long time, multiple types of treatments areused.4 Although treatment with the cysticidal agents albendazole and praziquantel has beenthe focus of a majority of reports, other treatments are also employed and important. Theseinclude use of corticosteroids and other immunosuppressive/anti-inflammatory medicationsto control damaging and potentially harmful host inflammatory responses, antiepilepticdrugs (AEDs), surgical interventions, and general supportive measures. Althoughcorticosteroids are commonly used to control signs and symptoms, their use has not beensystematically studied. Short-term use is associated with transient side effects that areusually tolerated; however, long-term treatment is commonly required in complicated NCC,and side effects are frequent, severe, and even life threatening.

Most of our current treatments are based on empiric observations and subsequentrefinements through clinical trials. We lack a scientific understanding of thepathophysiologic processes involved. Unraveling the basic mechanisms underlying theprocesses responsible for clinical disease expression and their interactions can be expectedto lead to novel, improved, and safer treatments to prevent short-term complications andlong-term sequelae. Three main basic processes take part in most of the disease and itsconsequences: 1) the biology of the cystic larva (growth, survival, degeneration, and death);2) the host inflammation directed to the larva (induction, type, character, and role inpathogenesis and clearance of parasite material); and 3) the nature and character of braindamage and genesis of seizures and epilepsy.

How cysts develop, survive, grow, and degenerate is poorly understood. However, these areimportant factors that determine the nature and complications due to cysticercosis.Inflammation is a dominant if not pivotal process in disease pathogenesis of most forms ofNCC. Seizures, the most common manifestation of NCC, somehow arise as a consequenceof this inflammatory process. In addition, the latter is the starting point of a series of eventsthat result in epilepsy. Knowing how seizures and epilepsy develop may lead to a betterunderstanding of the pathogenesis of other forms of epilepsy and rational methods to controlseizures in this population. A number of experts in parasitology, neurology, immunology,

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epilepsy, and veterinary medicine met last year to review the current status and issues in thetreatment of NCC. The goal of the conference was to determine ways to improve thetreatment of NCC by defining important questions and approaches to answer thesequestions. As the issues and problems associated with the frequently encountered differentclinical types of cysticercosis are unique, they are discussed separately below.

Intraparenchymal NCCViable cysts

Cysts most commonly lodge in the parenchyma of the brain. Parenchymal cysts may beviable, degenerating (enhancing lesions), or already dead and calcified.10 Viableparenchymal cysts may be asymptomatic. However, they are more frequently seen inpatients with seizures in endemic areas. Presumably, the viable cysts more frequentlydegenerate and initiate an injurious inflammatory response. Mass effects as well as focalneurologic symptoms and signs may also be caused by viable parenchymal cysts.

Many studies have documented that anthelmintic therapy results in death and resolution ofviable cysts,5,7-9,11,12 but the clinical benefit of this treatment had been questioned.6 Asnoted, treatment predictably injures cysts and initiates a sometimes intense inflammatoryresponse to them13 that mimics the natural evolution of cysts. Seizures, headaches, anduncommonly death can occur secondary to cysticidal treatments. Until recently it had beenunclear if it was better to kill cysts with anthelmintic agents and manage or prevent acutesymptoms at the time of treatment or not to employ anthelmintics, then intervene and treatsymptomatically as required. The recent publication of a randomized, placebocontrolled trialof treatment of adults with 20 or less viable parenchymal cysts and a history of seizures withalbendazole and a short course of corticosteroids showed long-term clinical benefit and adecrease in generalized seizures and a nonsignificant decrease in all seizures followingtreatment.7 Although earlier randomized controlled studies indicated clinical benefit oftreatment in some studies,7-9,12 others failed to reach significance.6

A recent meta-analysis of these treatment studies confirmed that anthelmintic treatment ofparenchymal NCC is clinically beneficial.14 This study and the reanalysis of prior studiesshift the prevailing opinion from one of disputed clinical benefit to one of proven efficacy oftreatment. The Garcia et al. multicystic treatment trial7 also found a correlation (althoughnot significant) between the presence of residual viable cysts and the occurrence of seizures.A number of studies earlier found correlations between the presence of viable ordegenerating cysts and increased risks of seizures.6,15-18 Though the Garcia et al. study is agood beginning in as much as it establishes the benefits of anthelmintic treatment of viablecysts, the magnitude of benefit demonstrated in the trial leaves much to be desired. Forinstance, it showed that only about half of the subjects irrespective of treatment remainedseizure-free over a 2.5-year period, and only one-third of the subjects were cured of theirdisease as shown by imaging at 6 months. This means that more effective treatments arerequired to maximize clinical benefit and reduce morbidity due to seizures.

One of the diagnostic hallmarks of NCC is the presence viable, degenerating, and calcifiedcysts in the same individual. Although some cysts are the focus of intense inflammatoryresponses, others have no or little associated host responses and can remain undisturbed forlong periods of time. Besides living in protected environments like brain and eye,mechanisms described to be associated with immune evasion in cysticercosis includecomplement inhibition, secretion of distractive antigens, cytokine expression, masking withhost's immunoglobulins, among others.19,20 Understanding how the parasite evades thehost's responses and other host-parasite interactions may lead to novel, safer, and moreeffective interventions. Studies are beginning to understand potential mechanisms that

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prevent effective host responses to viable cysts21 and how inflammatory responses to cystsprovoke seizures.22,23 However, therapies specifically designed to modify or prevent thedamaging inflammation caused by degenerating cysts have not yet been systematicallyevaluated.

Questions and approaches concerning treatment of viable cystsStudies need to identify and evaluate more effective, safe, and efficient anthelmintictreatments and the safest and most effective accompanying anti-inflammatory agents.Evidence from current studies suggests that the amount of time a patient is exposed to viablecysts that can potentially degenerate or to currently degenerating cysts correlates with anincreased risk of seizures. Therefore, methods to decrease the time at risk or to decrease therisk through judicious use of antiparasitic, antiinflammatory, or immunosuppressivetreatments should be studied.

Although both praziquantel and albendazole are proven cysticidal agents, their effectivenessis variable, and not all cysts die after a single course of antiparasitic treatment. This needs tobe improved with better regimens, better agents, or combinations of agents. Even thoughthere is a significant reduction in numbers of cysts, others survive and increase thelikelihood of seizures. The philosophy of treatment has been to use the least intervention interms of time and amount of drug to obtain reasonable cure rates in a majority but not allpatients. However, as the risk of seizures appears to correlate with the presence of viable anddegenerating cysts, consideration should be given to a more individualized goal ofeliminating all or almost all viable cysts where this approach is practical.

An understanding of the mechanisms of action of cysticidal medications may lead todevelopment and use of safer and more effective drugs or drug combinations. Oxfendazole,a drug that has been shown to be particularly useful in the treatment of cysticercosis inswine,24 and other potentially anticysticidal drugs should be evaluated in humans.Operationally, the methods of the trial by Garcia et al. can serve for initial comparison tooptimize therapy.7

The use of anti-inflammatory agents in cysticercosis has not been systemically studied, eventhough most experts favor the effectiveness of corticosteroids to one degree or another.4 Ifindeed seizures are associated with degenerating cysts and its associated inflammatoryresponses, then future research should address ways to prevent or minimize theseinflammatory responses. These include studies specifically designed to understand 1) howthe parasite remains viable and why there is no effective immune response; 2) whatmechanisms are involved in initiation of the host immune response; 3) characterization ofthe immune response; 4) which aspects of the host response are involved in pathogenesisand which lead to parasite clearance; and 5) appropriate and safe methods to controlinflammation associated with treatment-induced and naturally degenerating cysts.

Finally, studies need to address if and how treatment of viable cysts can lead to a decrease inepilepsy or seizures that is present in chronic cysticercosis, a later stage usually defined bythe presence of dead calcified cysts. Recent studies indicate that most of the morbidity inNCC occurs in chronic cysticercosis. Studies also need to address the evolution and naturalhistory of chronic cysticercosis and interventions to prevent and treat epilepsy associatedwith chronic disease.

Single enhancing lesionsA single degenerating cyst is the most frequent finding associated with NCC in the Indiansubcontinent25 and is common in other regions as well. Degenerating cysts are usuallyassociated with seizures because these cysts incite a granulomatous inflammatory response

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by the host. MRI of these lesions shows varying degrees of enhancement and edema, andhistologic examination of these as well as nodular enhancing lesions (a more advanced stageof degeneration) invariably shows acute and or chronic granulomatous inflammation.26-29

This type of presentation is the best studied of the clinical forms of NCC. Overall, there is afavorable prognosis. The effectiveness of antiparasitic treatments in this type of presentationhas been variable. However, the most rigorous double-blinded randomized treatment trialshowed an initial increase in seizures followed by a significant clinical benefit ofanthelmintic treatment compared to antiseizure medication over the subsequent 2 years ofevaluation.15,30 A nonblinded follow-up evaluation of treated and nontreated subjectsshowed an equalization of seizure frequency and an overall good prognosis in both groups.15

As mentioned earlier, reanalysis of treatment trials of enhancing lesions30-33 by meta-analysis showed an overall benefit of treatment.14 A potential reason for differences inindividual study results is the heterogeneity of morphology of single enhancing lesions(SELs). Some SELs have a cystic or vesicular appearance, whereas others appear nodular orsolid. Prior studies did not usually distinguish between these polar types of SELs. The cysticstage likely represents an early or nonresolving cyst in contrast to the solid nodular lesionsthat represent a more advanced state of degeneration and resolution. The former has beenshown to resolve with anthelmintic treatment.26 Treatment trials comparing fullydegenerated vs still cystic lesions may show more benefit of antiparasitic treatment in theseselected patients. A recently published randomized trial comparing 14 days of prednisolonein the absence of anthelmintic therapy with placebo documented a decrease in seizurefrequency in favor of prednisolone.34 However, another randomized open label trial foundthat prednisolone was significantly inferior in decreasing seizures compared withalbendazole and prednisolone.18 Although treatment with albendazole and prednisolone maybe superior to corticosteroid use alone, the former study34 is the best available informationthat judicious use of antiinflammatory agents are beneficial in decreasing seizures.34,35

Questions and approaches concerning treatment of SELsAlthough the long-term prognosis of these patients is relatively good with about 85%remaining seizure-free a mean of 65 months, in the absence of AEDs, 15% have recurrentseizures. Risk factors for recurrence are two or more seizures, breakthrough seizures, andresidual calcification16 or other lesions.15-18

SEL is one variety of NCC that is ideal for study because the natural history is welldescribed and its involution unaltered by the potential modifying influences of additionalparenchymal or extraparenchymal lesions. Given their frequency, measures to prevent thedevelopment of calcifications and chronic epilepsy are important. Last, although the follow-up and prognosis are known for about 5 years, this is a relatively short time in the life ofthese patients.

Chronic calcific cysticercosisEventually most parasites calcify, commonly appearing as punctate hyperdensities on CTexaminations. Brain calcifications typical of NCC are detected in from 15 to 20% ofendemic populations.36-41 Calcifications in the absence of viable cysts are frequently theonly or predominant type of lesion found in patients who present with seizures and havebeen implicated as seizure foci in studies. As treatment of viable cysts results in a decreasein the seizure rate, calcified and resolved cysts necessarily cause seizures at a lower rate thanviable and degenerating cysts. However, the number of individuals with calcifications islarge,36-41 and even though there is a relatively low frequency of seizures, there are aconsiderable number of affected persons.

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Previously, calcific NCC was characterized as “inactive,” implying it was not associatedwith significant disease or morbidity. Recently, perilesional edema around calcified lesionshas been detected around foci of seizure activity or focal neurologic deficits in symptomaticpatients (figure 1).42-44 How calcified cysticerci cause seizures or focal neurologicsymptoms is not understood. Although the overall importance and pathogenesis of thisphenomenon have not been well defined, preliminary evidence suggests episodicperilesional edema is common in this population.44 In addition, the presence of enhancementaround calcified lesions and the periodic presence of edema are suggestive of aninflammatory etiology, perhaps due to sporadic release of antigen and subsequent hostimmunologic responses.42-45

Questions and major approachesChronic cysticercosis as an important cause of seizures has only recently been appreciated,and consequently a reasonable understanding of its importance and knowledge of itspathogenesis are lacking. Prospective studies are required to determine the natural history,range of clinical manifestations, seizure frequency, and how best to prevent and treatassociated seizures in this group. A subset of patients presents with perilesional edema thatcan be frequent, recurrent, and life altering. The pathogenesis and whether the edemarepresents an inflammatory process or a response to focal epileptic activities are not known.A vexing question is why only a few of many lesions in the same individual are associatedwith perilesional edema and symptoms. There is no proven effective therapy so trials ofprevention and treatment are needed. A reasonable hypothesis is that prior inflammationsomehow generates a seizure focus. Enhanced measures to control inflammation or theresulting calcification induced by degenerating cysts may result in decreased rates ofseizures in chronic calcific cysticercosis. It has recently been suggested thatintraparenchymal calcifications alone can be toxic and promote seizures and headaches thatcan be reversed by calcium chelation with bisphosphonates.46 The association of NCC withmesial temporal lobe epilepsy due to hippocampal sclerosis may provide new insights intoepileptogenesis.47,48

Extraparenchymal NCCExtraparenchymal cysticercosis refers primarily to infection of the subarachnoid spaces andventricles. The clinical problems, approaches, and treatment differ from parenchymalinfection, and generally, the prognosis of these patients is worse compared with those withsolely parenchymal disease.49 Cysts may be small or large; the latter commonly present withlifethreatening mass lesions.49 They may or may not regress after anthelmintic treatment andin contrast to parenchymal cysts frequently require long-term and multiple courses ofanthelmintics.50 Meningeal inflammation is common and may lead to lacunar infarcts andhydrocephalus requiring placement of intraventricular shunts. However, shunt infection andfailure are common.51 There is a subset of patients who manifest persistent inflammationdespite prolonged if not heroic courses of treatment and seem to require continuous anti-inflammatory medication; most importantly, there are no controlled studies of treatment.

Subarachnoid cystsA subset of subarachnoid located cysts grows abnormally, presenting as large massoccupying lesions or as racemose cysts,52 which are aberrantly proliferating membranousforms (figure 2). Giant cysts respond to anthelmintic drugs. Inflammatory responses tosubarachnoid and ventricular cysts frequently cause chronic meningitis and ependymitis thatin turn result in hydrocephalus, a common long-term complication, necessitating shuntplacement. Lacunar infarcts and entrapment of cranial nerves occur as a result ofgranulomatous inflammation affecting adjacent arteries or nerves. Whether inflammation in

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chronic cysticercosis meningitis is the result of continuous degeneration or chronic antigenicrelease from dead parasitic tissues/ cells driving host inflammatory responses is not known.Inhibition of maturation, growth, and abnormal proliferation forms would be expected to beeffective treatments and result in better clinical outcomes.

Inflammation in subarachnoid cysticercosisThe importance of inflammation as a cause of morbidity and mortality is the most direct andobvious in subarachnoid and ventricular cysticercosis both from clinical observations andfrom autopsy examinations. Yet, very little is known about the nature of the inflammationand safe and effective measures to control it. The genesis of chronic inflammation despitelong-term anthelmintic treatment is not known. There are several potential contributors.First, CSF levels of both praziquantel and albendazole sulfoxide are erratic and influencedby other medications53 so that inadequate CSF drug levels may lead to continued parasitegrowth and degeneration that likely results in continued antigen release and subsequent hostinflammatory responses. Second, parasite materials may not be easily processed in thesubarachnoid space. Third, anthelmintic treatment may not be fully effective in the presenceof immunosuppressive medications. Other larval cestodes are capable of dissemination inimmunosuppressed humans or animals so that the idea of persons being chronicallyimmunosuppressed permitting some proliferation and antigen release is possible butcurrently without supporting clinical data.

Surgical choicesSurgery in subarachnoid NCC is mostly restricted to shunt placement or emergencydecompression. In the presence of acute obstructive hydrocephalus, surgical therapy can belifesaving. In many cases, this can be accomplished by placement of a ventricle–peritonealshunt. Case series suggest that shunt failure rates are high. However, the failure rate is lowerin cases treated with antiparasitic drugs. As viable cysts can mechanically obstruct ordegenerate and obstruct, surgical removal of cysts when feasible and safe seems areasonable approach. On the other hand, several authors have reported successfulantihelmintic treatment of giant subarachnoid cysts.50,54 Additionally, surgery has inherentadditional risks.

Questions and major approachesIssues such as the roles and uses of anthelmintics and antiinflammatory agents singly and incombination need to be assessed in subarachnoid and ventricular cysticercosis. Variablessuch as degree of drug absorption and CSF levels, degree of immunosuppression, andassessment of parasite presence/growth need to be controlled or measured to understandpossible roles in clinical outcome variability. Taenia antigens have been detected in serumand CSF of certain types of NCC.55-58 The presence and amount of Taenia antigen in theCSF or serum may correlate with presence and growth of subarachnoid cysts and beparticularly helpful in assessing presence, growth, and effectiveness of treatments.59 Thepractical usefulness of these tests needs to be shown and, if there is utility, assaysstandardized and made generally available. Subarachnoid or ventricular NCC is relativelyuncommon, and trials should require multicenter participation to obtain enough patients.Standardization of treatments for comparison is required.

Basic studies are needed to define the nature of the inflammatory process invoked byextraparenchymal larval cysts. Animal models using other cestodes, the infected pig, andhuman studies can be used to determine the characteristics of the inflammation and whatagents can safely control the inflammation over the time period required. In addition, therole of continued parasite regeneration or metabolism needs to be assessed using longer andshorter anthelmintic regimens in conjunction with immunosuppressive agents. Methotrexate

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has recently been reported to be an effective replacement or corticosteroid-sparing agent forlong-term control of meningeal inflammation.60 The development of effective and novelbiologic immunomodulatory agents offers the possibility of relatively specific and safer anti-inflammatory agents.

Given that anthelmintic treatments usually initiate an inflammatory response that commonlyrequires immunosuppression, one strategy that could be of benefit is surgical removal ofapproachable lesions that are large, likely to lead to long-term exposure toimmunosuppressives or anthelmintics, or to prevent complications. For instance, surgicalremoval of a large 3-cm-diameter cerebellar cyst encroaching on the fourth ventricle in thepresence of normal-sized multiple parenchymal cysts would be expected to minimize thepossible complications of medical treatment and the duration of therapy. The morbidity andmortality related to surgery would likely be less than the complications of long-termimmunosuppression and complications from a shunt, if it were required. How, when, andwhich cysts should be removed should be determined. Presumably cysts showing littleaccompanying inflammation or viable or unattached to the surrounding structures can beremoved with minimal damage to critical areas.

Ventricular diseaseCysts that lodge in the ventricles may result in hydrocephalus by blocking CSF flowmechanically or as a result of inflammation and fibrosis. Blockage of the fourth ventricleand to a lesser extent third ventricle is relatively frequent and gives rises to the most seriouscomplications. Cysts located in the lateral ventricles can cause unilateral hydrocephalus butmay also resolve without sequelae. Hydrocephalus is a common complication requiringplacement of intraventricular shunts. There are no randomized treatment trials comparingthe usefulness and safety of medical compared with surgical approaches.

Surgical choicesSurgery is mostly restricted to shunt placement or removal of cysts located in the ventricles.One series has shown that anthelmintic treatment of fourth ventricular cysts61 can beeffective. There are a number of convincing reports documenting the use of less invasiveflexible neuroendoscopy to remove approachable subarachnoid cysts and cysts lodged in thelateral, third, and fourth ventricles.62-65 These reports suggest that in the hands of trainedneurosurgeons, this method may be safer, faster, and perhaps more definitive andsubsequently may lead to better long-term clinical outcomes. Most intraventricular cystsseem to be freely floating and therefore may be extracted without trauma to the brain andavoid inflammation that would be elicited by anthelmintic therapy

Questions and major approachesThe role of anthelmintic therapy in ventricular cysts has not been adequately studied,although medical treatment is commonly suboptimal. It is likely that both medical andsurgical treatments are useful in ventricular NCC, but the conditions where each is best needto be defined. Trials comparing medical, surgical, or medical–surgical approaches arerequired. Important factors modifying approaches possibly include viability and location ofthe cyst, the urgency of the need for decompression, degree of accompanying inflammationand adherence to vital structures, and response to anti-inflammatory measures. Similar tosubarachnoid disease, there are a few reports suggesting that anti-inflammatory agents suchas corticosteroids and antiparasitic drugs are useful in preservation of intraventricularshunts. However, randomized trials, perhaps employing differing agents or regimens, areneeded.

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Seizure genesisIn recent studies, NCC is the cause of about one-third of all epilepsy and seizure cases inendemic areas. The risk of seizures is greatest in disease associated with viable ordegenerating cysts but continues to occur to a lesser extent in chronic calcific cysticercosis.Little is known about why and how seizures and epilepsy develop in this infection. There isreasonable information implicating host inflammatory responses. First, seizure focicommonly localize to inflamed or degenerating cysts. Histologic examination revealssurrounding inflammation, and concordant MRI studies demonstrate varying degrees ofcontrast enhancement or edema in contrast to viable cysts that show little or noinflammation by histologic examination or by MRI. This would be consistent with a recentstudy suggesting that disruption of the blood–brain barrier with leakage of serumcomponents into the brain is sufficient to induce seizures.66 Second, anthelmintic treatmentinitiates a host inflammatory response around cysts that mimics histologic and radiologicfindings typical of naturally degenerating cysts. Both are associated with an increased risk ofseizures. Third, in a small animal model, seizures were induced by the host response ratherthan the parasite itself.23 The rational for using corticosteroids during treatment is an attemptto control the inflammation and accompanying seizures.

Antiseizure medicationsAntiseizure medication is indicated in all patients with epilepsy and most with seizures.Although there is no information suggesting that use of AEDs in NCC differs from use inother similar types of epilepsy and seizures, this has not been formally studied. In addition,recent studies indicate that some AEDs may affect transcription through alteration ofhistones.67,68 Theoretically, they may affect the cyst directly and have effects on course oftreatment and even disease.

Questions and major approachesAs emphasized above, NCC is a common cause of seizures and epilepsy in endemicpopulations. Because cysticercosis is an acquired cause of epilepsy permitting prospectivestudies, seizure foci are commonly identifiable, and active and inactive foci can be directlycompared in the same patient, these patients are uniquely valuable to study the pathogenesisof epilepsy. Inflammation likely plays a pivotal role in the genesis of seizures and epilepsy.Use of model infections in pigs for instance and sophisticated neuroimaging studies inafflicted patients can be expected to yield an understanding of important basic processes.

General recommendationsThere was overall agreement in support of the following general recommendations: 1)support by international health organizations for the development for multicenter clinicaltrials; 2) organization of multidisciplinary treatment units; 3) recognition that understandingof basic pathophysiologic mechanisms including survival, growth, and degeneration of theparasite, nature and character of the inflammatory response, and the genesis of seizures,epilepsy, and mechanisms of anthelmintic action will lead to safer, specific, and moreeffective therapies; and 4) development of noninvasive neuroimaging to assess the natureand degree of inflammation and location and state of the larval cestodes and neuroexcitation.NCC continues to be a major cause of neurologic disease in most of the world. Despite theimportance and associated burden of disease (mainly related to chronic, many timesdisabling neurologic symptoms), key pieces of knowledge are still missing, hamperingattempts to optimize clinical care.

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AcknowledgmentsSupported by the Office of Rare Diseases (NIH), National Institute of Allergy and Infectious Diseases/Laboratoryof Parasitic Diseases (NIH), Universidad Peruana Cayetano Heredia (Lima, Peru), and Instituto de CienciasNeurologicas (Lima, Peru).

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Figure 1.Brain edema surrounding a calcified cyst as seen on CT (left) and MRI (right).

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Figure 2.Extraparenchymal (basal subarachnoid) cysticercosis.

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Treatment of neurocysticercosis: Current status and future research needs

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